Ethyl Acrylate (EA) is a known forestomach carcinogen in both rats and mice. Early work in this laboratory indicated that carcinogenic doses of EA administered by gavage for 13 weeks resulted in a sustained increase in forestomach epithelial cell proliferation as long as exposure to EA continued. However, hyperplasia regressed and no forestomach neoplasms were seen after a 19 month recovery period. Current studies were designed to further investigate the time required for sustained hyperplasia to lead to neoplasia as well as the organ specificity of EA-induced cell proliferation/hyperplasia Vs carcinogenicity. EA was administered at 200 mg/kg (p.o.) to male F344 rats, 5 days/week. Squamous cell proliferation/hyperplasia was observed in the forestomach of all rats which received EA for 6 or 12 months. Treatment of rats with EA for 12 months followed by 2 months recovery resulted in the development of forestomach papillomas in 2 of 5 treated rats. Further, animals treated for 12 months and allowed 9 months recovery exhibited an increase in forestomach squamous cell carcinomas and papillomas at a combined incidence of 4/13. In contrast, animals treated with EA for 6 months and allowed 2 or 15 months recovery exhibited a time-dependent regression of cell proliferation and did not develop forestomach neoplasms. No significant elevation in liver cell proliferation or neoplasia was seen at any time in any of the rats included in the present study; further confirming the organ specificity in the relationship between EA-induced cell proliferation and carcinogenicity. In conclusion, EA resulted in increased cell proliferation in the target organ of carcinogenicity (forestomach) but not in non-target organs such as the liver. This work indicates that cell proliferation, sustained for a sufficient period of time, results in the development of neoplasia despite cessation of chemical administration. Further, a temporal relationship exists between EA- induced epithelial cell proliferation and forestomach carcinogenicity.